| For medical practitioners and the general public - Cholesterol Journal Article Catalog. |
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| Increased susceptibility to activation and increased uptake of low density lipoprotein by cholesterol-loaded macrophages Oiknine, J. and M. Aviram (1992), Arterioscler Thromb 12(6): 745-53. Abstract: Inflammation is associated with macrophage activation, and this process has been shown to occur during atherogenesis. Macrophages (J774A.1) that were activated with either lipopolysaccharide (LPS), zymosan, or phorbol ester demonstrated a 30-35% increased uptake and degradation of low density lipoprotein (LDL) in comparison with nonactivated cells. This phenomenon was also shown for LDL cellular binding, and it resulted in macrophage cholesterol accumulation, as evidenced by cholesterol mass determination and flow cell cytometric analysis. Enhanced uptake of LDL was also obtained with two other types of macrophages: mouse peritoneal macrophages and human monocyte-derived macrophages. In LPS-stimulated macrophages, high density lipoprotein-mediated cholesterol efflux was not different from that shown in nonstimulated cells. Cellular cholesterol synthesis, however, was increased by 25% in the activated macrophages. Macrophage activation, measured as cellular procoagulant activity, was higher in cholesterol-loaded than in nonloaded cells. On stimulation of cholesterol-loaded macrophages, cellular uptake and degradation of LDL were increased by 3.3-fold in comparison with nonactivated cholesterol-loaded cells. Human monocyte-derived macrophages from hypercholesterolemic patients were found to contain 52% more cholesterol mass than macrophages derived from normal healthy donors. These cells demonstrated increased activation (twofold) in response to LPS stimulation and also showed 25% enhanced cellular degradation of LDL. We conclude that activation of macrophages during atherogenesis can lead to foam cell formation, and this mechanism is probably operative in hypercholesterolemic patients. |
| Increased synthesis of cholesterol stearate in flanking organ from gonadectomized female hamsters treated with progesterone and 5 alpha-dihydroprogesterone Cabeza, M. and R. Miranda (1997), Proc West Pharmacol Soc 40: 87-9. Abstract: We demonstrated for the first time that progesterone and 5 alpha-dihydroprogesterone stimulate U-14Cglucose incorporation into lipids in gonadectomized female hamster flanking organs. We also found that cholesterol stearate is the major lipid synthesized female hamster flanking organs under progesterone and 5 alpha-dihydroprogesterone stimulation. In this manner, progesterone and 5 alpha-dihydroprogesterone alter the consistency of sebum from gonadectomized female glands. |
| Increased transglutaminase in the aortas of cholesterol-fed rabbits: occurrence of buffer soluble and insoluble forms and an inhibitor Wiebe, R. I., A. H. Tarr, et al. (1991), Biochem Cell Biol 69(12): 821-7. Abstract: Rabbits were fed for 10-12 weeks on a normal pellet diet or on the same diet containing 1% cholesterol and 6% peanut oil. The animals were killed and the aortas divided into three layers which were homogenized and extracted. The extracts and the insoluble residues were assayed for transglutaminase activity and tissue transglutaminase antigen. When compared with normal aortas, the inner and middle layers of aortas with atherosclerotic lesions from cholesterol-fed rabbits showed higher transglutaminase activities in the buffer-soluble fraction without a corresponding increase in antigen. The buffer extracts showed two peaks (I and II) of activity and antigen on DE 52 chromatography; peak I was also found, together with lipid, in Triton X-100 extracts of the buffer-insoluble residue. The Triton X-100 insoluble fraction showed higher concentrations of both activity and antigen in the inner and middle layers of atherosclerotic aortas than in normal aortas, but the activity per nanogram of antigen was lower than in the buffer-soluble fraction. The activity in this insoluble residue was largely extracted, together with an inhibitor, by an NaCl-sucrose-dithiothreitol-Triton X-100 solution. DE 52 chromatography of this extract showed a third peak of activity and antigen (peak III) and an inhibitor peak that was distinct from the activity peaks. |
| Increased triglycerides and/or low HDL cholesterol. A risk factor needing treatment? Steinmetz, A. (2002), MMW Fortschr Med 144(31-32): 20-3. Abstract: Elevated LDL (low density lipoprotein) cholesterol is considered an established risk factor for the development of atherosclerotic sequelae. In this context, low HDL cholesterol and/or raised triglyceride levels are now also receiving increasing attention as independent risk factors for atherosclerosis. The protective HDL cholesterol should be as high as possible (> 40 mg/dl or 1.0 mmol/l). Low HDL cholesterol levels are associated with an increased coronary risk that cannot be eliminated by lowering LDL cholesterol concentrations. Measures to elevate HDL are primarily dietary adjustments, cessation of smoking, weight reduction and increased physical activity. Triglyceride levels above 1000 mg/dL are also associated with an increased risk for the development of pancreatitis, and therefore also need to be treated. |
| Increased type II transforming growth factor-beta receptor expression in liver cells during cholesterol challenge Baccante, G., G. Mincione, et al. (2000), Atherosclerosis 152(1): 51-7. Abstract: A large body of evidences implicates transforming growth factor-beta (TGF-beta) in the pathogenesis of atherosclerosis. In this context, TGF-beta receptor dysfunction has been suggested to be relevant. We tested the effect of hypercholesterolemia, a well-known risk factor for atherosclerosis, on liver type II TGF-beta receptor (TbetaR-II) expression in atherosclerosis-susceptible C57BL/6 mouse strain fed atherogenic diet. In addition, the relationship between cholesterol and TbetaR-II expression was verified by cholesterol challenge on human hepatoma cell (HepG2) cultures. The susceptible C57BL/6 mice fed atherogenic diet exhibited significant mRNA and immunohistochemical TbetaR-II liver expression at 2, 5, 9 and 15 weeks as compared to animals fed a regular diet. The TbetaR-II profile on HepG2 resulted in a time-dependent increased expression when the cells were incubated with soluble free cholesterol, associated with an increased TGF-beta-dependent biological activity as detected by luciferase assay of reporter gene. These data provide evidence for a cholesterol-dependent TbetaR-II induction that may play a potentially relevant role in the development of hypercholesterolemia and atherogenesis. |
| Increased uncoupling protein2 mRNA in white adipose tissue, and decrease in leptin, visceral fat, blood glucose, and cholesterol in KK-Ay mice fed with eicosapentaenoic and docosahexaenoic acids in addition to linolenic acid Hun, C. S., K. Hasegawa, et al. (1999), Biochem Biophys Res Commun 259(1): 85-90. Abstract: The effects of n-3 polyunsaturated fatty acids (n-3PUFA) on obesity and diabetes were examined using KK-Ay mice fed with perilla oil (P), soybean oil (S), or lard (L), and those containing 30% fish oil (PF, SF, or LF), containing eicosapentaenoic acid (EPA = 9.9%) and docosahexaenoic acid (DHA = 18.0%). Perilla oil contained the largest proportion of linolenic acid (LNA = 61.9%). Computerized tomography (CT) scans showed narrower areas of visceral fat in the abdominal cross sections of groups given fish oil (PF, SF, and LF) and lower leptin levels (p < 0.05-p < 0.001) compared with controls (P, S, and L), without significant changes in energy intake and body weight. The highest plasma n-3PUFA content (21.31 +/- 0.35%) was attained with PF. This group contained 2.6-fold more plasma DHA (p < 0.001), and expressed 2.7-fold more UCP2 mRNA in white adipose tissue (p < 0.01) than in the P group. The epididymal fat pad (p < 0.05) weighed less, and levels of blood glucose (p < 0.05) and total cholesterol (p < 0.01) were reduced in PF compared with P. |
| Increases in biliary cholesterol-to-bile acid ratio in pregnant hamsters fed low and high levels of cholesterol Yao, L., P. A. Dawson, et al. (2003), Am J Physiol Gastrointest Liver Physiol 284(2): G263-8. Abstract: Gallstones develop when the secretion of cholesterol is elevated compared with the secretion of bile acids into bile. One of the risk factors for the formation of gallstones is pregnancy. Because the pregnancy-induced increase in hepatic cholesterol synthesis rates could play a critical role in the development of cholesterol stones, the aim of the present study was to determine whether stone formation, as assessed by the ratio of cholesterol to bile acids in bile, could be ablated by blocking the pregnancy-induced increase in hepatic sterol synthesis rates. Golden Syrian hamsters were fed either ground chow or chow supplemented with 0.5% cholesterol for 3 wk and studied in the nonpregnant state or in late gestation. In chow-fed animals, a 1.6-fold increase in the ratio of cholesterol to bile acids occurred simultaneously with a sevenfold increase in hepatic sterol synthesis rate and a ninefold increase in the amount of newly synthesized cholesterol secreted into the bile in late gestation. In the cholesterol-fed dams, an increase in the ratio of cholesterol to bile acids occurred even with the lack of induction of hepatic sterol synthesis rates during pregnancy. Thus it appears that the marked induction of hepatic sterol synthesis rates during gestation is not essential for the pregnancy-induced cholesterol saturation of bile when cholesterol is fed to animals. |
| Increases in cholesterol 7-hydroperoxides in lipids of human skin by sunlight exposure Yamazaki, S., N. Ozawa, et al. (1999), Free Radic Biol Med 26(9-10): 1126-33. Abstract: Free and ester forms of cholesterol 7alpha- and 7beta-hydroperoxides (Ch 7-OOHs) in skin lipids of humans were separated and determined by high performance liquid chromatography with a chemiluminescence detector. We first demonstrated the presence of Ch 7-OOHs in lipids of human skin. The levels of Ch 7-OOHs found in skin lipids of healthy Japanese volunteers (n = 5) ranged from 2.78 to 25.2 pmol/cm2 skin, indicating large inter-individual differences. However, the intra-individual differences of Ch 7-OOHs levels in skin lipids between right and left arms were less than 25% (-16.4% to 24.0%). Inter-day differences of Ch 7-OOHs in 5 subjects at 1 week interval were also small (-36.7% to 47.7%). Additionally, we investigated effects of sunlight exposure on the levels of Ch 7-OOHs in skin lipids of healthy Japanese volunteers (n = 24). The levels of Ch 7-OOHs in skin lipids significantly increased from 10.0+/-6.7 to 38.9+/-38.0 pmol/cm2 skin by sunlight exposure (10-40 mJ/cm2/min) for 3 h. Therefore, natural sunlight exposure causes lipid peroxidation in skin lipids of humans. These results suggest that the level of Ch 7-OOHs is a good marker for lipid peroxidation in human skin. |
| Increases in depression after cholesterol-lowering drug treatment Davidson, K. W., S. Reddy, et al. (1996), Behav Med 22(2): 82-4. Abstract: To investigate the possibility that increases in depressive symptoms might occur in patients who have undergone cholesterol-lowering interventions, the authors administered the Center for Epidemiological Studies-Depression scale before and after cholesterol lowering to 6 men who were referred to a lipid clinic. All of the patients' cholesterol levels were reduced after the 6-week intervention, and 4 of the patients' depression scores increased; scores of 2 of the 4 met the criteria for mild clinical depression. Further study of possible links among low cholesterol, depressive symptoms, and serotonergic activity is needed. |
| Increases in dietary cholesterol are associated with modest increases in both LDL and HDL cholesterol in healthy young women Ginsberg, H. N., W. Karmally, et al. (1995), Arterioscler Thromb Vasc Biol 15(2): 169-78. Abstract: We studied the effects of dietary cholesterol intake on lipid and lipoprotein levels in healthy young women (n = 13) who were otherwise eating an American Heart Association (AHA) diet. The study used a randomized, three-way crossover design to determine the effects of 0, 1, or 3 eggs added per day (dietary cholesterol range, 108 to 667 mg/d). Each of the three diets was eaten for 8 weeks, with a washout period between diets. Three fasting blood samples were obtained during the last 3 weeks of each diet period to observe changes in fasting plasma lipid levels associated with the menstrual cycle. We also obtained blood just before and 4 and 8 hours after the subjects ingested a standard high-fat formula. During the menstrual cycle, total cholesterol and LDL cholesterol levels fell by 0.051 mmol/L (1.99 mg/dL) and 0.064 mmol/L (2.48 mg/dL) per week, respectively. HDL cholesterol concentrations increased by 0.060 mmol/L (2.3 mg/dL) per week during the first half of the cycle and then fell by 0.050 mmol/L (1.94 mg/dL) per week during the second half. Therefore, all statistical analyses were performed on values adjusted to midcycle. Total fasting cholesterol concentrations increased by 0.073 mmol/L (2.81 mg/dL) per 100 mg dietary cholesterol added to the diet per day (P =.001). LDL cholesterol increased by 0.054 mmol/L (2.08 mg/dL) per 100 mg/d dietary cholesterol (P =.003); this accounted for about 75% of the rise in total cholesterol. HDL cholesterol concentrations increased by 0.015 mmol/L (0.57 mg/dL) per 100 mg/d dietary cholesterol (P <.04). There was a wide range of responses among the women. Plasma apoB levels increased significantly, 0.93 mg/dL per 100 mg/d dietary cholesterol (P =.025), whereas apoA-I levels tended to rise (1.35 mg/dL per 100 mg/d, P =.056). Increases in dietary cholesterol did not produce any observable effects on fasting plasma cholesteryl ester transfer protein levels and had no effect on the response to a standard high-fat formula. Although menstrual-cycle changes in plasma total, LDL, and HDL cholesterol levels were observed, the effects of the diets were similar in the follicular and luteal phases of the menstrual cycle. Additionally, despite changes associated with the menstrual cycle, within-subject variation in plasma total cholesterol was actually smaller in this study than in our study of young men. |
| Increases in serum non-high-density lipoprotein cholesterol may be beneficial in some high-functioning older adults: MacArthur studies of successful aging Karlamangla, A. S., B. H. Singer, et al. (2004), J Am Geriatr Soc 52(4): 487-94. Abstract: objectives: To examine the association between changes in serum non-high-density lipoprotein cholesterol (non-HDL-C) over a 2.5-year period and risk of adverse health outcomes in the following 4.5 years in high-functioning older adults. DESIGN: Prospective cohort, established in 1988, with a follow-up in 1991 and 1995. SETTING: Population-based, community-dwelling men and women. PARTICIPANTS: A random sample (n=267) from the MacArthur cohort (N=1,189). The cohort represented the highest-functioning tertile of 4,030 screened candidates aged 70 to 79. MEASUREMENTS: Change in non-HDL-C between 1988 and 1991 was measured as a predictor of health outcomes between 1991 and 1995, including all-cause mortality, and among survivors, incident heart attack or stroke, development of new disability in basic activities of daily living, and decline in performance on the Short Portable Mental Status Questionnaire. RESULTS: More-positive change in non-HDL-C between 1988 and 1991 was associated with fewer adverse outcomes between 1991 and 1995. In individuals whose total cholesterol at baseline was in the middle two quartiles (195-244 mg/dL), each 10-mg/dL increase in the 1988-to-1991 change in non-HDL-C was associated with an adjusted mortality odds ratio (OR) of 0.67 (95% confidence interval (CI)=0.51-0.88). In individuals without cardiovascular disease at baseline, the adjusted OR for new physical disability was 0.79 (95% CI=0.65-0.95) and for cognitive decline was 0.81 (95% CI=0.67-0.98). CONCLUSION: Increases in cholesterol over time have beneficial associations in some older adults. The role of cholesterol changes in the health of older individuals needs further exploration. |
| Increasing age alters transbilayer fluidity and cholesterol asymmetry in synaptic plasma membranes of mice Igbavboa, U., N. A. Avdulov, et al. (1996), J Neurochem 66(4): 1717-25. Abstract: Previous studies examining age differences in membrane fluidity and cholesterol content have reported on the average or total change in membrane structure, respectively. However, a membrane consists of an exofacial leaflet and a cytofacial leaflet that differ in fluidity and cholesterol distribution. The purpose of the present experiments was to determine fluidity and cholesterol distribution of the exofacial and cytofacial leaflets of brain synaptic plasma membranes (SPMs) from 3-4-, 14-15-, and 24-25-month old C57BL/6NNIA mice by using trinitrobenzenesulfonic acid (TNBS)-quenching techniques and fluorescent probes. The exofacial leaflet of SPMs from young mice was significantly more fluid compared with the cytofacial leaflet. The large difference in fluidity between the two leaflets was abolished in SPMs of the oldest age group. Total SPM cholesterol and the cholesterol-to-phospholipid molar ratio did not differ among the three different age groups of mice. However, considerable differences were observed in the distribution of cholesterol in the two SPM leaflets. The exofacial leaflet contained substantially less cholesterol than did the cytofacial leaflet (13 vs. 87%, respectively) in SPMs of young mice. This asymmetric distribution of cholesterol was significantly modified with increasing age. There was an approximately twofold increase in exofacial leaflet cholesterol in the oldest group compared with the youngest age group. Transbilayer fluidity and cholesterol asymmetry were altered in SPMs of older mice. This approach is a new and different way of viewing how aging modifies membrane structure. Age differences in SPM leaflet structure may be an important factor regulating activity of certain membrane proteins. |
| Increasing amounts of dietary myristic acid modify the plasma cholesterol level and hepatic mass of scavenger receptor BI without affecting bile acid biosynthesis in hamsters Loison, C., F. Mendy, et al. (2002), Reprod Nutr Dev 42(2): 101-14. Abstract: The purpose of this study was to analyze the effects of increasing amounts of dietary myristic acid (0.03 to 4.2% of the total dietary energy) on the plasma and hepatic cholesterol metabolism. Six groups of hamsters received semi-purified diets containing 0.05% cholesterol and 12.5% lipids and differing only by the nature of the triglycerides (Safflower oil, lard, lard/coconut oil (1:1), milk fat, milk fat/coconut oil (1:1), coconut oil) for 3 weeks. A positive regression between the plasma cholesterol level and the dietary myristic acid level was observed (r = 0.60, P < 0.0001). However, it is noteworthy that the increase in plasma total cholesterol only reflects an increase in the level of HDL-cholesterol. In parallel, the mass SR-BI decreased linearly with the increased level of myristic acid in the diet, whereas the LDL-R did not change. This study shows that increasing amounts of myristic acid (0.03 to 4.2%) do not alter the cholesterol or bile acid metabolism and increase only the HDL-C. |
| Increasing dietary cholesterol induces different regulation of classic and alternative bile acid synthesis Xu, G., G. Salen, et al. (1999), J Clin Invest 103(1): 89-95. Abstract: We investigated the effect of increasing dietary cholesterol on bile acid pool sizes and the regulation of the two bile acid synthetic pathways (classic, via cholesterol 7alpha-hydroxylase, and alternative, via sterol 27-hydroxylase) in New Zealand white rabbits fed 3 g cholesterol/per day for up to 15 days. Feeding cholesterol for one day increased hepatic cholesterol 75% and cholesterol 7alpha-hydroxylase activity 1.6 times without significant change of bile acid pool size or sterol 27-hydroxylase activity. After three days of cholesterol feeding, the bile acid pool size increased 83% (P < 0.01), and further feeding produced 10%-20% increments, whereas cholesterol 7alpha-hydroxylase activity declined progressively to 60% below baseline. In contrast, sterol 27-hydroxylase activity rose 58% after three days of cholesterol feeding and remained elevated with continued intake. Bile drainage depleted the bile acid pool and stimulated downregulated cholesterol 7alpha-hydroxylase activity but did not affect sterol 27-hydroxylase activity. Thus, increasing hepatic cholesterol does not directly inhibit cholesterol 7alpha-hydroxylase and initially favors enzyme induction, whereas increased bile acid pool is the most powerful inhibitor of cholesterol 7alpha-hydroxylase. Sterol 27-hydroxylase is insensitive to the bile acid flux but is upregulated by increasing hepatic cholesterol. |
| Increasing effect of dietary taurine on the serum HDL-cholesterol concentration in rats Mochizuki, H., H. Oda, et al. (1998), Biosci Biotechnol Biochem 62(3): 578-9. Abstract: Taurine, 2-amino ethanesulfonic acid, is the major free intracellular amino acid present in many tissues and plays an important role in lipid metabolism such as that of bile acid conjugation for fat absorption. The effect of taurine on the serum cholesterol level in normal rats was investigated. Taurine enhanced the serum HDL-cholesterol concentration in a dose-dependent manner without any change in total cholesterol. |
| Increasing HDL Cholesterol Levels Brewer, H. B., Jr. (2004), N Engl J Med 350(15): 1491-4. |
| Increasing HDL cholesterol with extended-release nicotinic acid: from promise to practice Birjmohun, R. S., B. A. Hutten, et al. (2004), Neth J Med 62(7): 229-34. Abstract: BACKGROUND: The inverse relation between high-density lipoprotein cholesterol (HDL-C) and cardiovascular (CV) disease underscores the need for clinical evaluation of the effect of HDL-C increasing drugs on the prevalence of CV disease. METHODS: We review the efficacy of Niaspan on serum lipids and the occurrence of side effects either alone or in combination with statins, in randomised controlled trials (RCT) and comparative cohort trials (CCT). RESULTS: In four RCTs, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG) and lipoprotein(a) (Lp(a)) were decreased by 13, 26, and 17%, respectively, whereas HDL-C increased by 18%. In four CCTs a combination of Niaspan and statins showed an additional 22% reduction in LDL-C, 8% in TG and 6% in Lp(a) levels, compared with Niaspan monotherapy. Statin therapy had a minor additional effect of 1% on a total of 25% HDL-C increase during Niaspan treatment. Flushes occurred in 69% of the patients without any additional toxicity during combination therapy. CONCLUSION: Niaspan effectively raises HDL-C with concomitant beneficial effects on TG and LDL-C. Niaspan can be combined safely with statins and is also effective in patients with combined dyslipidaemia and type 2 diabetes mellitus. Trials on CV endpoints evaluating the effect of statins with Niaspan are urgently needed to settle whether this combination can confirm the high expectations for cardiovascular outcome. |
| Increasing hepatic cholesterol 7alpha-hydroxylase reduces plasma cholesterol concentrations in normocholesterolemic and hypercholesterolemic rabbits Xu, G., G. Salen, et al. (1996), Hepatology 24(4): 882-7. Abstract: The effect of bile acid depletion and replacement with glycodeoxycholic acid on plasma cholesterol concentrations, hepatic low-density lipoprotein (LDL) receptor binding and messenger RNA (mRNA) levels, and hepatic activities and mRNA levels for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7alpha-hydroxylase was investigated in 19 New Zealand white (NZW) and 15 Watanabe heritable hyperlipidemic (WHHL) rabbits. Bile acid depletion was produced by external bile drainage for 5 days, which maximized cholic acid synthesis. Replacement was achieved by infusing glycodeoxycholic acid intraduodenally for 24 hours so that the hepatic bile acid flux reached prefistula levels. Plasma and liver cholesterol concentrations were 13 times and 50% greater, respectively, hepatic LDL receptor-mediated binding was 26% less, and cholesterol 7alpha-hydroxylase activity and mRNA levels were 62% and 86% less in WHHL than NZW rabbits. After bile drainage, plasma cholesterol concentrations decreased 29% in NZW rabbits and 40% in WHHL rabbits and were associated with a 2.1-fold increase in hepatic LDL receptor-mediated binding in the NZW rabbits, but there was no change in the WHHL rabbits. Cholesterol 7alpha-hydroxylase activity and mRNA levels increased three and four times in NZW and WHHL rabbits, respectively, although liver cholesterol levels remained unchanged. Replacement with exogenous glycodeoxycholic acid increased plasma cholesterol concentrations 1.7 times in NZW rabbits and decreased enhanced cholesterol 7alpha-hydroxylase activity 54%, mRNA levels 86%, cholic acid synthesis 38%, and hepatic LDL receptor-mediated binding 57% in NZW rabbits. Bile acid depletion stimulated cholic acid synthesis by up-regulating cholesterol 7alpha-hydroxylase to use cholesterol and reduce plasma concentrations substantially in both NZW and WHHL rabbits, although LDL receptors did not function in WHHL rabbits. Glycodeoxycholic acid replacement inhibited elevated cholesterol 7alpha-hydroxylase, cholic acid synthesis, and hepatic LDL receptor binding to reestablish baseline plasma cholesterol levels in NZW rabbits. Hypercholesterolemia in WHHL rabbits was related to the combination of dysfunctional LDL receptors and inhibited cholesterol 7alpha-hydroxylase. Plasma cholesterol concentrations were reduced significantly when cholesterol 7alpha-hydroxylase was stimulated even in the absence of LDL receptor function. |
| Increasing high-density lipoprotein cholesterol: an update on fenofibrate Despres, J. P. (2001), Am J Cardiol 88(12A): 30N-36N. Abstract: The inverse relation between coronary artery disease and the concentration of high-density lipoprotein cholesterol (HDL-C) is well established. A low HDL-C concentration is frequently accompanied by the features of the metabolic syndrome found in patients with type 2 diabetes and in individuals who are abdominally obese. Results from 3 independent trials are consistent in showing that fenofibrate is able to increase HDL-C levels across a wide range of dyslipidemic states. The HDL-C-increasing effect of fenofibrate is proportionately greater when baseline levels are low. Comparing results from published trials, the absolute increase in HDL-C produced by fenofibrate is greater than that with statins across all baseline HDL-C levels, and a 40-mg/dL treatment target HDL-C level is more likely to be achieved with fenofibrate therapy. Fenofibrate has favorable pleiotropic effects on several features of the metabolic syndrome, which are likely to explain the clinical benefits of fibrate therapy, beyond an impact on HDL-C levels. The additional reciprocal beneficial effect of fenofibrate in lowering low-density lipoprotein cholesterol (LDL-C) benefits those patients with low HDL-C and moderately increased LDL-C; the American Diabetes Association now recommends fibrate therapy in this case. Another trial, the Diabetes Atherosclerosis Intervention Study (DAIS) has also provided angiographic evidence to show that fenofibrate treatment may slow coronary artery disease progression in type 2 diabetes. Treatment effects on apolipoproteins suggest that not all fibrates affect HDL-C to an equal degree. A trial with fenofibrate focusing on coronary artery disease risk and mortality reduction in patients with type 2 diabetes that is currently under way, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial is expected to report in 2005. |
| Increasing plasma fibrinogen, but unchanged levels of intraplatelet cyclic nucleotides, plasma endothelin-1, factor VII, and neopterin during cholesterol lowering with fluvastatin Gottsater, A., I. Anwaar, et al. (1999), Blood Coagul Fibrinolysis 10(3): 133-40. Abstract: Lipid-lowering statin treatment reduces cardiovascular morbidity and mortality and improves endothelial function in patients with hypercholesterolemia. The aim of the present study was to evaluate plasma levels of fibrinogen, factor VII, and the macrophage-derived inflammatory mediator neopterin during lipid lowering. In addition, the endothelial production of platelet antiaggregatory and vasodilatory factors such as nitric oxide and prostacyclin, and vasoconstrictive factors such as endothelin-1, was assessed. Plasma fibrinogen, factor VII, endothelin-1, and the neopterin and intraplatelet nitric oxide and prostacyclin mediators cyclic 3'-5'guanosine monophosphate (cGMP) and cyclic 3'-5'adenosine monophosphate (cAMP) were measured before and 6 months after the institution of treatment with fluvastatin in 17 patients (eight men and nine women, median age 60 years) with vascular disease and previously untreated hypercholesterolemia. After 6 months, a decrease of 1.62 mmol/l 1.26-2.18 (19%); P < 0.01 was noted in levels of total cholesterol, and a decrease of 1.70 mmol/l 1.52-2.30 (28%); P < 0.01 in levels of low-density lipoprotein cholesterol. Plasma levels of fibrinogen had increased from 4.81 g/l (4.26-5.27) to 5.17 g/l (4.81-5.67); P < 0.05, whereas no significant changes had occurred in intraplatelet levels of cGMP decrease by 0.05 pmol/10(9) platelets (-0.17 to 0.24); NS, cAMP decrease by 0.13 pmol/10(9) platelets (-0.37 to 0.86); NS, plasma endothelin-1 decrease by 0.05 pg/ml (-0.60 to 0.70); NS, plasma factor VII from 1.14 IE/ml (0.58-1.38) to 1.22 IE/ml (0.96-1.46); NS, or plasma neopterin from 8.6 nmol/l (7.1-11.5) to 8.7 nmol/l (7.9-11.3); NS. In conclusion, during cholesterol-lowering treatment with fluvastatin, plasma levels of fibrinogen increased whereas intraplatelet cyclic nucleotide levels and plasma endothelin-1, factor VII and neopterin levels were unchanged. |